Genetic, neuropathological, and biochemical evidence has implicated an increased steady-state abundance as well as aberrant processing of α-synuclein (αS) in the development of several neurodegenerative disorders including Parkinson disease (PD), dementia with Lewy bodies (DLB), and others (Dawson et al., (2003) Science, 302:819-22; Vila et al., (2004) Nat Med., 10 Suppl:S58-62).
Genetic evidence demonstrates that point mutations in the α-synuclein-encoding gene are linked to a severe, dominantly-inherited form of PD with early onset (Krueger et al., (1997) Nat. Genet., 18, 106-108; Zarranz et al., (2004) Ann. Neurol., 55(2):164-73; Polymeropoulos et al., (1997) Science, 276:2045-7), implying a “toxic-gain-of-function” pathogenesis. These mutations cause the following amino acid changes: alanine 30→proline (A30P), glutamine 46→lysine (E46K), and alanine 53→threonine (A53T). Furthermore, duplication and triplication of the α-synuclein encoding synuclein, alpha (non A4 component of amyloid precursor) gene (SNCA) have been linked to familial parkinsonism with a combined PD/DLB phenotype, which demonstrates that increased expression rates of even the wild-type (wt) gene can cause disease (Chartier-Harlin et al., (2004) Lancet, 364, 1167-9; Singleton et al., (2003) Science, 302, 841). Intriguingly, certain polymorphisms within the promoter region of the SNCA gene have also been linked to increased risk for sporadic, late-onset PD (Pals et al., (2004) Ann. Neurol., 56, 591-5; Maraganore et al., (2006) JAMA, 296, 661-70).
Neuropathological evidence indicates that the intra-neuronal inclusions termed Lewy bodies and Lewy neurites, which represent one of the pathological hallmarks of PD and DLB seen at autopsy, contain high levels of aggregated α-synuclein protein (Spillantini et al., (1998) Proc Natl Acad Sci USA, 95, 6469-73; Baba et al., (1998) Am. J. Pathol., 152, 879-884). These aggregates are generally viewed as the result of cellular mis-handling of α-synuclein protein (possibly related to post-translational events, such as hyper-phosphorylation (Anderson et al., (2006), J. Biol. Chem., 281, 29739-29752) and intracellular accumulation as both soluble toxic oligomers and insoluble fibrils (Sharon et al., (2001), Proc Natl Acad Sci USA, 98, 9110-9115).
In addition, biochemical evidence suggests that overexpression of α-synuclein in cellular or animal systems may cause cellular stress and/or eventual death through a variety of mechanisms, including—among others—excess dopamine concentration and reactive oxygen species generation (Tabner et al., (2002), Free Radic. Biol. Med., 32(11):1076-83; Fahn et al., (1992), Ann. Neurol., 32, 804-12) as well as mitochondrial dysfunction (Lee (2003), Antioxid. Redox Signal, 5:337-48; Hashimoto et al., (2003), Neuromolecular Med., 4(1-2):21-36). Published PCT patent application WO 07084737 discloses treating lysosomal storage disorders having central nervous system implications with lysosomal enzymes.